Underactive Bladder: A New Entity in Voiding Dysfunction?

Overactive bladder (OAB) is a very common urologic entity and complaint among urologic patients.  OAB represents a constellation of symptoms including urgency, with or without incontinence, frequency and nocturia.[1]  See our prior blog entry on Female Incontinence for more details on OAB.  There are a number of causes of OAB and subsequently OAB can be related to a variety of coincident urologic diagnoses like bladder outlet obstruction in men, pelvic organ prolapse in women, neurologic or systemic diseases like diabetes.  In addition, OAB has a number of excellent treatments progressing from behavioral therapy (i.e. modifying fluid intake) to medications, and finally surgical devices (like Interstim or Tibial Nerve Stimulation).

Underactive bladder (UAB) is similar to OAB in that it represents a constellation of symptoms and has a number of etiologies and coincident urologic diagnoses.  Symptoms of UAB are strangely similar to OAB and can include:

• urgency
• frequency
• nocturia
• hesitancy
• straining to void
• sensation of incompete voiding
• urinary retention
• incontinence (overflow or urgency)

UAB may occur without symptoms or associated diseases.  However, some associated diseases and causes of UAB (are once again similar to OAB and) include:

• neurologic disease
• muscle disease or failure (includes the detrusor (bladder) muscle or muscles of the pelvic floor)
• age-related
• medication-related
• bladder outlet obstruction (most commonly benign prostatic hyperplasia in men) [2,3]

Unlike OAB, there are no good treatments for UAB.  Therefore UAB remains an underappreciated entity and therefore is lacking in understanding and concensus regarding its diagnosis and treatment.  Previous attempts at classifying UAB used the terminology detrusor underactivity (DU) to indicate an inability of the detrusor (or bladder) muscle to contract with enough force to expel urine.  Recent studies indicate the UAB is more common than previously predicted.

• In a study of 1,179 men and women older than 65 years-old with non-neurogenic voiding dysfunction and lower urinary tract symptoms (LUTS) [4]
• 40% of men and 13.3% of women had DU (similar to UAB)
• the proportion of patients with DU increased with age
• A study of 181 elderly patients with LUTS identified DU in 48% of men and 12% of women. [5]
• 40% of men in this study had bladder outlet obstruction (BOO), only 10% of men with DU had BOO

UAB can notably cause long-term, chronic issues including urinary retention requiring catheterization, urinary incontinence and/or recurrent urinary tract infections.  

Therefore the First International CURE-UAB (Congress of Urologic Research and Education on UnderActive Bladder) was held in Washington, DC in February 2014 in the hopes of addressing some of the shortcomings in the uderstanding of UAB.  The CURE-UAB was founded and led by David Chancellor, BS, Vikas Tyagi, MD and Michelle Gruber, BS.  Over 100 health care experts met at the congress to discuss, define and outline research goals for the future of UAB.  The meeting and subsequent research is funded by the NIH (National Institutes of Health).  To find out more about UAB, visit the website: http://www.underactivebladder.org/

[1] Chapple CR, Artibani W, Cardozo LD, et al. The role of urinary urgency and its measurement in the overactive bladder symptom syndrome: current concepts and future prospects. BJU Int 2005;95:335–40.
[2] van Koeveringe GA, Vahabi B, Andersson KE et al: Detrusor underactivity: a plea for new approaches to a common bladder dysfunction.  Neurourol Urodyn 2011; 30: 723.
[3] Osman NI, Chapple CR, Abrams P et al: Detrusor underactivity and the underactive bladder: a new clinical entity? A review of current terminology, definitions, epidemiology, aetiology, and diagnosis. Eur Urol 2014; 65: 389.
[4] Jeong SJ, Kim HJ, Lee YJ et al: Prevalence and clinical features of detrusor underactivity among elderly with lower urinary tract symptoms: a comparison between men and women. Korean J Urol 2012; 53: 342.
[5] Abarbanel J and Marcus EL: Impaired detrusor contractility in community-dwelling elderly presenting with lower urinary tract symptoms. Urology 2007; 69: 436.

Historical Contribution: 1935, Lewis, Langworthy & Dees, Motor Pathways of the Bladder

1935

Bladder abnormalities due to injury of motor pathways in the nervous system L. G. Lewis, O. R. Langworthy and J. E. Dees. Journal of the American Medical Association, 1935.

Little was known about the nervous innervation of the bladder in 1935.  A constellation of symptoms and a number of deficits were attributed to injuries to the sensory pathways of the bladder.  While two motor pathways were described: one from the cerebral cortex and one from the midbrain (the pontine micturation center), the subsequent deficits were not well understood.

To investigate the motor innervation of the bladder, Lewis, Langworthy and Dees create a precursor to the modern cystometrogram (urodynamics) - a relatively simple device made of a catheter and manometer filled with water and coupled to a recording device (see figure).  The authors catalogue the findings in a normal patient a demonstrate low-pressure filling and a normal sensation at around 200cc of water.















The authors then investigate and describe the outcomes of patients with three distinct patterns of voiding:

1. Bilateral cortical lesions (lesion #1) - leading to a small capacity bladder and involuntary contractions.
2. Unilateral cortial lesions (lesion #2) - patients with left-sided lesions had normal bladder capacity, those with right-side lesions had decreased bladder capacity leading the authors to believe that bladder control was heisphere-dominant.
3. Spinal cord injuries (lesion #3) - these patients demonstrated a variety of findings, all of which demonstrated abnormal filling, volumes and contractions.  

In summary, they make a number of important observations that define function of the urinary system:

• Normal micturition depends on a steady rise of bladder pressure of sufficient strength and duration to empty the viscus completely. When waves occur rhythmically and frequently, they do not have the strength or duration for efficient emptying.
• The cerebral cortex controls the smooth muscle of the bladder, enabling the bladder to hold large amounts of fluid at a relatively low pressure (below the level of discomfort). Without conrtical control, bladder capacity decreases and frequency of urination is common.
• Many of the frequency and urgency symptoms following neurologic injury can be considered as uninhibited smooth muscle reflexes (analagous to a "knee-jerk" reflex).

To read the entire manuscriptclick on the title above or click here.


HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Surgery for Testicular Cancer: Orchiectomy

While scrotal ultrasound and serum tumor markers (beta-human chorionic gonadotropin, alpha-fetoprotein, and lactate dehydrogenase) are the first steps in the diagnosis of a testis cancer, the diagnosis is not confirmed until an orchiectomy (surgical removal of the testicle) is performed.  The standard-of-care for the removal and treatment of testis cancer is a radical orchiectomy.  This is the most common operation performed for testis cancer worldwide. However, as our understanding of this disease and surgical technique has improved, testis-sparing surgery or partial orchiectomy has become an option for some patients.

This blog entry will briefly discuss important considerations for men undergoing orchiectomy for testis cancer.

RADICAL ORCHIECTOMY

Rationale

This surgery involves removing the testicle and spermatic cord where it exits the body to identify and likely treat the majority of cancers localized to the testis.  As a male fetus develops, the testes develop near the fetal kidneys.  As the fetus grows, the testicles separate from the kidneys and, at about the eighth month of pregnancy, the testicles exit the body wall to rest in the scrotum (this is why premature infants have a higher likelihood of having undescended testicles).  Therefore the blood supply, lymphatic drainage and nerves to the testicle originate near the kidney on that side.  Once these structures exit the body through the internal inguinal ring they fuse with muscles of the body wall to form the spermatic cord.  To correctly stage and prevent any cancer from spreading, the spermatic cord must be taken as high toward or inside the body as possible -- hence the incision in the groin rather than the scrotum.

For men whose cancer has spread from the testicle and who have metastatic testis cancer (elsewhere in the body) or in the lymph nodes of the retroperitoneum, radical orchiectomy is an important first step in the diagnosis and management of disease.  Knowing the type of cancer may help guide chemotherapy or radiation treatments.

Surgery

Adapted from Gottesman JE. In: Crawford ED, editor.
Current genitourinary cancer surgery.
Philadelphia: Lea & Febiger; 1990. p. 319.

The surgery can be performed under general or local anesthetic.  An approximately 5-10cm incision is made in the groin, just above the pubic tubercle (pubic bone) near the inguinal ligament.  This incision facilitates access to both the testicle and the proximal inguinal canal.  The skin incision is relatively painless, so a larger incision should be made to facilitate delivery of a large testicular tumor or to help with access to the spermatic cord.  The incision is carried down to the external oblique fascia (the outermost layer of the body wall).  The external oblique creates a tunnel through which the spermatic cord travels -- a hernia can form when there is weakness in these layers of the body wall.  Once the external oblique fascia is identified, the cord can then be identified exiting the external spermatic ring.  The cord should be isolated and the external fascia will need to be opened to gain access to the internal ring and to take the spermatic cord where it exits the body.  This can be done in either order.  Care should be taken to separate and preserve the ilioinguinal nerve which travels along the spermatic cord.  Once the cord is isolated, an occlusive, but non-crushing clamp or elastic drain can be used to stop blood supply to and from the testicle.  This prevents any "shedding" of tumor cells when the testicle is manipulated.  The testicle can then be "delivered" from the scrotum.  To deliver the testicle the scrotum can be inverted until the testicle is visible, facilitating dissection of the testicle from its scrotal contents.

Once the testicle and spermatic cord are entirely free from the inguinal canal, the testicle can be removed.  The spermatic cord should be ligated in two packets - one containing the gonadal artery and one containing the vas deferens (sperm duct) and its associated artery.  A large, non-absorbable suture should also be tied to the distal spermatic cord to facilitate easy identification in the case that a retroperitoneal lymph node dissection needs to be performed in the future.  Care should be taken to close the external oblique fascia to the level of the external ring to prevent future hernia.

Complications

The biggest risk of a radical orchiectomy is hematoma (or bleeding into the scrotum).  It is very common for the scrotum to be bruised, swollen and tender for 2-4 weeks after surgery.  However, a large, purple-appearing scrotum can indicate a hematoma.  Hematoma can be prevented with a compressive dressing, tight-fitting undergarments and/or ice packs.
Ilioinguinal nerve injury can occur if the nerve is damaged during dissection of the spermatic cord.  This is more common in men who underwent prior inguinal surgery (usually for an undescended testicle or hernia repair) and can occur during dissection or be inadvertently trapped in the closure of the external oblique fascia.  The deficit is often decreased sensation to the medial thigh, scrotum or base of the penis.  It is often transient, but can take several weeks or months to improve.
Inguinal hernia can occur if the external oblique fascia is not closed properly or if the closure breaks down.  It is important to minimize strenuous activities for 2-4 weeks to prevent development of a hernia.

Made by Coloplast. 

Testicular Prosthesis

Prostheses should be offered to all men undergoing orchiectomy.  Not all men want a prosthesis -- it is a personal decision.  The prosthesis should be measured in the operating room with the patient asleep.  The goal should be to match the remaining testicle in size taking into account a cancerous testicle can be larger or smaller than normal, and the scrotal skin will make a prosthesis look larger once implanted.

TESTIS-SPARING SURGERY (PARTIAL ORCHIECTOMY)

Rationale

While radical orchiectomy remains the standard-of-care for the diagnosis and treatment of testis cancer, there are a couple of circumstances where testis-sparing surgery is advocated.  The primary indications are in men with:

• bilateral testis cancers (either synchronous, at the same time; or metachronous, that develop some time after the first testicle is removed)
• the standard-of-care would be to remove both testicles under suspicion of cancer, however the implications regarding fertility and testosterone replacement are well-established
• small, palpable testis masses and normal serum tumor markers
• these men have a low, but significant risk of having a benign mass or non-germ cell cancer that does not require orchiectomy
• if a testis cancer is confirmed, a radical orchiectomy is completed
• small, non-palpable, ultrasound detected testis mass with normal tumor markers
• approximately 80% likelihood of benign mass [1] 

Some urologists advocate for testis-sparing surgery even for men with germ cell tumors of the testicle.  While some evidence indicates that this can be done safely in some patients, it is not a proven or well-established technique.[2,3]  Before undergoing testis-sparing surgery, an extensive consultation should occur with the patient and their family regarding expectations and possible outcomes in the operating room.

Surgery

Tumor being identified with
intra-operative ultrasound.

The beginning portion of a testis-sparing surgery is identical to a radical orchiectomy.  Once the testicle is "delivered," the testis-sparing portion should begin.  The tunica vaginalis should be opened vertically to expose the testicle and intraoperative ultrasound should be used to identify the mass, rule-out other masses and create a surgical plan.  The testicle should be iced down for 10 minutes prior to placing a tourniquet or non-crushing clamp on the spermatic cord.  Once the testicle has been iced, a clamp or tourniquet should be placed on the cord.  The tunica albuginea (which houses the tubules of the testicle) should be opened horizontally above the mass.  The mass can often be "shelled" out of the surrounding tubules with a margin of 3-5mm.  Surgical loupes or a microscope can be used to facilitate dissection with a clean margin.  Bipolar forceps can be used to control any bleeding to prevent injury to the remaining tubules.  The mass should then immediately go to pathology for frozen analysis - an expert genitourinary pathologist should evaluate the mass when possible.

If the patient has a normal contralateral testicle and cancer is confirmed in the mass, a completion radical orchiectomy should be performed.

Tumor (in clamp) being dissected from normal testis.

If the patient has (or had) cancer in the contralateral testicle, the pathologist should confirm negative margins before leaving the remainder of the testicle.  If any suspicion of residual cancer, the testicle should be removed.  Once again, the standard-of-care is bilateral orchiectomy and testosterone can easily be replaced.

Complications

The complications are the same for radical orchiectomy and testis-sparing surgery.  In addition, even if testis-sparing surgery is performed, surgery can result in infertility or hypogonadism if the internal blood supply to the testicle is harmed or if the tubules are disrupted.

Summary

Radical orchiectomy is the standard-of-care for men with suspicion of testis cancer and is therefore the most common operation done for testicular cancer.  Testis-sparing surgery (or partial orchiectomy) is a novel approach suitable for some patients.

Phillip M. Pierorazio, MD is the Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  










[1] Giannarini G, Dieckmann KP, Albers P, Heidenreich A, Pizzocaro G.  Organ-sparing surgery for adult testicular tumours: a systematic review of the literature.Eur Urol. 2010 May;57(5):780-90. doi: 10.1016/j.eururo.2010.01.014. Epub 2010 Jan 20.
[2] Brunocilla E, Gentile G, Schiavina R, Borghesi M, Franceschelli A, Pultrone CV, Chessa F, Romagnoli D, Ghanem SM, Gacci M, Martorana G, Colombo F.  Testis-sparing surgery for the conservative management of small testicular masses: an update.  Anticancer Res. 2013 Nov;33(11):5205-10.
[3] Leonhartsberger N, Pichler R, Stoehr B, Horninger W, Steiner H.  Organ preservation technique without ischemia in patients with testicular tumor.  Urology. 2014 May;83(5):1107-11. doi: 10.1016/j.urology.2013.12.021. Epub 2014 Feb 21.

Additional References/Resources:
Joel Sheinfeld MD and George J. Bosl MD.  Surgery of Testicular Tumors in Campbell-Walsh Urology, Tenth Edition. 2012,  871-892.

Donald A. Elmajian and Dennis D. Venable.  Radical orchiectomy in Hinman's Atlas of Urologic Surgery, Third Edition.  2012. 353-356.

New AUA Guidelines for Kidney Stones

Brian Matlaga, MD

The American Urological Association (AUA) recently released GUIDELINES FOR THE MEDICAL MANAGEMENT OF KIDNEY STONES.  Kidney stones are a common problem in the United States and are a disease with a high-rate of recurrence.  There are well-proven, effective treatments for the prevention of kidney stones.  However there is evidence that these treatment regimens are underutilized.  Brian Matlaga, MD, Associate Professor of Urology and Director of Stone Disease at the Brady Urological Institute was a member of the guideline committee tasked with standardizing the treatment of kidney stones.  Here he reviews some of the important features of the new Guideline.  Salient point are broken down into Evaluation, Dietary Therapies, Pharmacologic Therapies and Follow-Up.  Important studies are referenced.

EVALUATION

All patients with a newly diagnosed stone should undergo a screening evaluation.
This should include a dietary and medical history, serum chemistry evaluation, urinalysis and urine culture, and a stone analysis.

Important aspects of the medical history include signs, symptoms and comorbidities associated with stone disease (renal tubular acidosis, primary hyperparathyroidism, diabetes, gout, obesity); a dietary history (fluid, calcium, protein and fruit/vegetable intake); and pertinent medications (topiramate, zonisamide, acetazolamide, triamterene, probenecid, protease inhibitors, vitamin C).

When examining a serum chemistry:

• high calcium and low phosphate can indicate primary hyperparathyroidism
• a serum parathyroid hormone level should be checked only if primary parathyroidism is suspected
• low bicarbonate, low potassium and increased chloride may indicate distal renal tubular acidosis
• increased uric acid can indicate low pH or hyperuricosuria

A stone analysis should be obtained at least once for a patient with stones:

• cystine stones indicate cystinuria
• uric acid stones identify low urinary pH as a target for treatment
• struvite stones may coincide with recurrent urinary tract infections

24-hour metabolic testing should be completed in high-risk patients, interested first-time stone formers and recurrent stone formers.  This is based on data that supersaturation levels in 24-hour urinalyses consistently reflect stone composition and preventive treatments can result in reduction of supersaturation levels in most patients.[1]  

"High-risk" stone formers include those with:

• Family history 
• GI disease/bowel resection
• Gout
• Type II diabetes mellitus
• Obesity
• Distal renal tubular acidosis
• Primary hyperparathyroidism
• Nephrocalcinosis
• Recurrent urinary tract infections
• Children or adolescents
• Solitary kidney

DIET THERAPIES

Clinicians should recommend that all stone formers:

• increase fluid intake to achieve a urine volume of 2.5L each day.  
• limit sodium intake
• consume 1000-1200 mg/day of dietary calcium [2,3]  

Patients with uric acid stones, or calcium stones with high urinary uric acid, should limit intake of animal protein.

PHARMACOLOGIC THERAPIES

Thiazide diuretics should be offered to patients with high or relatively high urinary calcium and recurrent calcium stones.[4]
Potassium citrate should be offered to all patients with recurrent calcium stones and low urinary citrate.[5]
Thiazide diuretics and/or potassium citrate should be offered to patients with recurrent calcium stones and no other identifiable metabolic abnormalities.[6]

Allopurinol should be offered to patients with recurrent calcium oxalate stones, hyperuricosuria and normal urinary calcium.  Allopurinol should not be offered as first-line therapy to patients with uric acid stones, rather treatments to alter urinary pH should be considered.

FOLLOW-UP

Urinary parameters are believed to precede stone recurrence, therefore serial urine collections should be obtained to assess changes in stone risk factors.  Success of any treatment should therefore be gauged by improvement in urinary risk factors and ultimately into reduction in stone events.

-----

This blog entry was extracted from a recent presentation by Brian Matlaga, MD, the AUA GUIDELINES FOR THE MEDICAL MANAGEMENT OF KIDNEY STONES.  The Guideline Committee was led by Margaret S. Pearle, MD, PhD, Chair, and David S. Goldfarb, MD, Vice-chair.  To read the entire Guideline Document click on the link above or here.

-----
[1] Parks et al, KI 51: 894, 1997

[2] Borghi et al, J Urol 155: 839, 1996

[3] Borghi et al, NEJM 346:77, 2002

[4] Pearle, Roehrborn et al, J Endourol 13, 1999

[5] Barcelo et al, J Urol 150: 1761, 1993

[6] Ettinger et al, J Urol 158: 2069, 1997

Historical Contribution: 1934, Waters, Lewis & Frontz, Radiotherapy for Renal Cancer

1934

Hohman LB, Scott WW. A Combined Psychiatric and Urologic Study of Sexual Impotenct. Southern Medical Journal. 1933;29;1:59-76.

This manuscript starts with a case description, a 52 year-old man presents with a large renal mass, palpable "It is evident in this case we were dealing with an extremely radiosensitive tumor."  
through his abdomen, firm to the touch and extended 11cm beneath the margin of his ribs.  He was treated with external radiotherapy in preparation for surgery, but never came back to the hospital for nephrectomy.  He lived greater than 5 years without additional treatment, prompting the authors to conclude,

Today we know that renal cell carcinoma is actually an extremely radioresistant tumor.  However, this manuscript is a fascinating look into the understanding of renal cell carcinoma in 1934.  Here are some salient points made by the authors:

• Radiation was often used in cases that were felt unresectable or in the presence of metastatic disease.  Marked reduction in the size of the primary tumor was observed in many of these cases.
• Size reduction was almost immediate.
• Delay in surgery resulted in regrowth of tumor.
• Because imaging techniques were poor, response to radiation was measured by palpation.
• "...the percentage of cures will probably not be materially increased until earlier diagnosis makes possible the institution of treatment before metastases has occurred."
• hematuria as the first symptom should call for a thorough evaluation of the urinary tract.
• Radiosensitivity is based on tumor cell type, with "tumors that revert to the embryonic type of growth and present a considerable degree of anaplasia are most radiosenstive" -- an observation made by Ewing.
• Renal cortical tumors (hypernephromas) demonstrated a fair response with regard to size.
• Renal pelvis tumors (papillary urothelial tumors) did not respond to radiation.
• In addition, papillary renal cell carcinomas did not respond to radiation; "there were no areas of necrosis, no large cysts, and no blood-filled spaces."

• Interestingly, necrosis was a common finding after irradiation - without a control group, it makes you wonder how many large, renal cortical tumors have necrosis as a baseline.
• At the doses of radiation given, there were no changes to the normal renal parenchyma surrounding the tumors, but doses were limited by side effects: skin erythema and nausea.
• However, extensive morphological changes were noted in the radiosensitive tumors with fibrosis, hyalinization and necrosis.  
• The nephrectomy in patient case number 2 was performed by leaving "pedicle clamps" in place for 9 days after surgery before removing them - without an issue!
• The authors highlight a number of important oncological principles of time (some still current):
• minimize palpation of the tumor to prevent shedding of tumor cells
• the renal pedicle should be ligated prior to manipulation (for the same reason)

Click here or on the link above to read the entire manuscript.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Fluorescence Cytology (Cysview) for Bladder Cancer: A look at the evidence

For patients with bladder tumors, a key step in evaluation is the identification and complete removal of the entire bladder mass.  A complete transurethral resection of bladder tumor (TURBT) however, is easier said then done, as nearly 30% of patients will have residual cancer after a primary resection.  Recently, the fluorescent contrast-agent, hexaminolevulinate (HAL, Cysview®), was FDA-approved to enhance white light cystoscopy in detecting Ta/T1 bladder tumors, and carcinoma-in-situ (CIS) in particular.  As 50% of patients with CIS will go on to have disease progression, enhancing the identification of CIS will decrease delays to treatment, and ultimately to disease progression in the long run. Here we will review several key concepts related to the use of Cysview during cystoscopy and tumor resection.

How does fluorescence cytology work?

HAL is preferentially absorbed by cancer-cells than normal urothelial (lining) cells of the bladder.  A sufficient amount of HAL is absorbed in about an hour.  When exposed to "blue-light illumination" the HAL is visibly seen as a bright, fluorescent lesion.  More details can be found at the Cysview website.
Practically, the HAL solution is instilled into the bladder via a urethral catheter at least 1 hour prior to surgery.  In the operating room, the urologist can perform both standard, "white light" cystoscopy and "blue light" cystoscopy in the examination of the bladder.

An ideal case from the Cysview.com Clinical Library Atlas:
http://www.cysview.com/clinical-library/atlas/

What is the key evidence that HAL (Cysview) works?

Stenzl et al. Hexaminolevulinate Guided Fluorescence Cystoscopy Reduces Recurrence in Patients with Nonmuscle Invasive Bladder Cancer.  J. Urol. 2010

In this prospective, randomized study, 814 patients with suspected Ta/T1 disease on outpatient cystoscopy were divided into groups receiving standard white light cystoscopy versus HAL (Cysview) based cystoscopy.  280 patients in the white light cystoscopy group and 271  in the fluoresce cystoscopy group were followed with cystoscopy for 3, 6, and 9 months following initial resection or until recurrence.  This study demonstrated that HAL (Cysview) improved detection of Ta or T1 tumors in 16% of patients, and improved identification of CIS in 32% of patients whose cancer was not detected with white light.  Several patients in the study had Ta lesions identified with white light and concurrent CIS detected only with HAL (Cysview), an important finding given the divergent treatment paradigms for Ta and CIS lesions.

Grossman et al.  Long-term reduction in bladder cancer recurrence with hexaminolevulinate enabled fluorescence cystoscopy J. Urol. 2012

In this long term follow up of the study described above, the authors found that median recurrence free survival was 9.6 months in the white light group and 16.4 months in the HAL (Cysview) group.  With a median follow up of 55 months and low overall numbers of patients with disease progression, there was no statistical difference between rates of upstaging (T2-4 disease) or cystectomy.  However, the white light group had double the patients with upstaging and cystectomy, and as follow up is extended in the future these results may prove significant.

Burger et al.  Photodynamic Diagnosis of Non-muscle-invasive Bladder Cancer with hexaminolevulinate Cystoscopy:  A Meta-analysis of Detection and Recurrence Based on Raw Data. Eur Urol 2013.

In this metanalysis of 9 studies, the authors demonstrated that  HAL (Cysview) detected 14.7% more Ta bladder tumors and 40.8% more CIS lesions.  Similarly, recurrence rates at 12 months in the pooled dataset were 35% in the HAL (Cysview) group versus 45% in the white light group

What are the barriers to HAL (Cysview) implementation?

Currently, the use of HAL (Cysview) can only be undertaken when partnered with the Karl Storz D-light system and not with other manufacturers.  Though likely temporary, this constitutes a market inefficiency and a barrier to widespread adoption

What are the remaining questions with HAL (Cysview)?

It is clear that HAL (Cysview) accurately detects bladder cancer.  It is not clear exactly how much, if at all, "blue light" cystoscopy is better than standard, "white-light" cystoscopy.  A number of important questions remain:

• Will HAL (Cysview) eliminate the need for a “2nd look” TURBT?  Currently, even in the best of hands, standard, "white light" cystoscopy and TURBT leaves cancer behind or misses muscle-invasion in 10-20% of patients.  Therefore, standard practice and the AUA (American Urological Assocation) Guidelines recommend a 2nd procedure to ensure all cancer has been resected.  It is not yet known if HAL (Cysview) can improve outcomes of primary TURBT and alleviate the need for a 2nd look TURBT.  
• Does HAL (Cysview) detect clinically-significant cancers (i.e. cancers that will change management)?  From the evidence in the studies above, we know that blue light cystoscopy will find more cancers than white light cystoscopy.  However, many of these cancers a non-invasive cancers and similar to other, known lesions in the same patient.  In some patients HAL (Cysview) can certainly make a difference - it is not clear who these patients are.
• Will HAL (Cysview) ultimately lead to increased bladder preservation due to more complete and earlier resections?  This will likely be answered with greater follow up in the next few years as earlier randomized studies mature.

HAL (Cysview) is an emerging technology with the potential to change the way bladder cancer in managed.  As clinical experience and knowledge is gained regarding its use and patient outcomes, its role will be more clearly defined.  If suspicious of a bladder cancer, or there is a history of or known cancer, feel free to talk to your urologist about HAL (Cysview) and blue light cystoscopy.  However, HAL (Cysview) and blue light cystoscopy may not be of benefit and therefore, is not for every patient.



This blog was written by Max Kates, MD, a URO-2 resident at the Brady Urological Institute at Johns Hopkins.

Penile Cancer: Basics of Diagnosis and Staging

Penile cancer, in general, refers to cancer of the skin of the penis.  Most of these cancers (95%) are squamous cell carcinoma (SCC), similar to skin cancers elsewhere on the body.  Men can also develop cancers of the urethra (or inner lining of the penis), but this is a distinct and separate entity.  In the United States, penile cancer is relatively rare affecting only about 1,600 men - about 0.2% of the nearly 1 million male cancers diagnosed each year.  The incidence of penile cancer varies around the world and can reach as high as 20% of all male cancers in some African countries and Brazil.

The variation in the incidence of penile cancer is related to risk factors.  The best known risk factors for penile cancer include:

• phimosis (circumcision is protective of penile cancer in regions where rates are high)
• poor hygiene (obesity may be a risk factor if it prevents good hygiene)
• smegma (trapped male penile secretions)
• tobacco use
• Human Papilloma Virus (HPV) 16*, 18, 31 and 33

The worldwide rates of penile cancer are decreasing and this is attributed to improved education regarding hygiene, improving socioeconomic status and may be attributed to increasing rates of circumcision.

Penile cancer most often present as a lesion on the penis.  The majority of cancers appear on the glans (or head) or the prepuce (foreskin) of the penis.  

48% Glans

21% Prepuce

9% Gland and Prepuce

6% Coronal Sulcus

2% Shaft

There are a number of pre-malignant lesions that may dispose a man to later development of penile cancer.  The lesions range from the dysplastic to carcinoma-in-situ to frank squamous cell carcinoma.  We review some of the more common lesions below:

DYSPLASTIC LESIONS

Balanitis Xerotica Obliterans (BXO)

Balanitis Xerotica Obliterans (BXO)

Appears as a whitish plaque on glans or prepuce

Can cause meatal stenosis 

4-8% will progress to SCC 

Treatment: topical steroid cream, circumcision, meatotomy (opening of the urethral meatus) if needed

Leukoplakia 

solitary or multiple whitish plaques often associated with chronic irritation

10-20% will progress to SCC

Treatment: surgical excision w/ long term F/U

Condyloma Accuminata

Condyloma accuminata (veneral warts)

Associated with HPV 6 and 11

Flat lesions, can be identified easily as they turn white with 5% acetic acid soaks

Treatment: topical podophyllin, CO laser ablation, IFN injection

Buschke-Lowenstein tumor (verrucous carcinoma)

Also associated with HPV 6 and 11

Locally destructive, but does not metastasize 

Treatment: local excision

Carcinoma in situ (CIS)

carcinoma in situ (CIS)

Carcinoma in situ is classified by its appearance and location on the penis.

Erythoplasia of Queyrat 

red, velvety, well demarcated lesion of glans/prepuce

10-33% progress to invasive SCC

Not associated with visceral malignant disease

Treatment: local excision/circumcision, laser fulgration, topical 5FU

Bowens disease 

sharply defined plaques of scaly erythema on shaft

5% progress to invasive SCC

Metastases are rare but are reported

Bowens disease is associated with an increased risk of concomitant visceral malignancy (commonly prostate or bladder cancer)

Treatment: local excision, close follow up

Diagnosis and Evaluation

Most lesions present while localized to the penis.  Physical examination is of paramount importance as staging (depth of spread; see below) is most important in determining prognosis.  Lesions that are mobile and in the skin have a better prognosis than lesions that are fixed or growing into the deeper structures of the penis.  The first location of spread for penile cancer is to the lymph nodes in the groin.  50% of patients with have enlarged lymph nodes in the groin at the time of presentation.  However, only 50% of these patients will have cancer in the lymph nodes as these lymph nodes are often "reactive" to inflammation or super-infection in the penile lesion.  Interestingly, 20% of patients without palpable lymph nodes will eventually be determined to have metastatic cancer.

The most important step in the evaluation of a penile lesion is biopsy.  Biopsy can either be incisional (a sampling) or excisional (the whole lesion is removed).  Both dermatologists and urologists are proficient in biopsy in most hospitals.  Biopsy is essential to rule out or confirm a diagnosis of SCC, assess the depth of invasion (stage), determine grade (aggressiveness) of the cells and evaluate for microscopic vascular invasion (predictive of distant recurrence).  Depth of invasion, or tumor stage, is the most important factor in the initial evaluation of penile cancers.    

Staging of the Primary Tumor (T-stage) 

Tx – cannot be assessed

T0 – no primary tumor

Tis – CIS

Ta – noninvasive verrucous carcinoma

T1 – subepithelial connective tissue invasion

T1a: no LVI, NOT poorly differentiated 

T1b: + LVI, grade 3-4 (poorly differentiated)

T2 – invaded corpus spongiosum, cavernosum

T3 – invades urethra

T4 – other adjacent structures

Interestingly, stage and grade are highly correlated.  Grade describes the aggressiveness of the cancer under the microscope and high grade cancers are more likely to be locally invasive and more likely to have spread to the lymph nodes in the groin.  Up to 25% of low-grade tumors will have lymph node involvement; 40-90% of high-grade tumors will have positive lymph nodes.  Nodal stage is determined by the size and location of enlarged and involved lymph nodes.

Nodal Stage (N-Stage)

NX cannot be assessed

N0 – no palpable or visibly enlarged inguinal nodes

N1 – palpable, mobile unilateral inguinal lymph node (single lymph node)

N2 – palpable, mobile multiple or bilateral inguinal lymph nodes

N3 – extranodal extension of LN mets or pelvic lymph nodes (uni/bilateral)

  

REFERENCES

American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.

Penile Cancer. American Cancer Society.  http://www.cancer.org/cancer/penilecancer/index

Pettaway, Lance and Davis.  Tumors of the Penis.  Campbell-Walsh Urology , Tenth Edition. 2012. Eds Wein, Kavoussi, Novick, Partin, and Peters.  Chapter 34, 901-933.e9